The long term goals of this research project are to understand the interplay of cellular processes contributing to neuronal and glial cell zinc ion homeostasis in the human central nervous system. In addition we will elucidate the underlying mechanisms of any changes in cellular zinc ion homeostasis that occur in neurodegenerative disorders such as Alzheimer's disease. This pilot grant application proposes experiments that will provide much needed new information on the mechanism of plasma membrane zinc ion influx and efflux in the human brain. Further, we will identify any changes in plasma membrane zinc transport that are associated with Alzheimer's disease pathology. These data will then form the basis of a subsequent RO1 application focused towards accomplishing our long term goals. Published studies from this laboratory have provided convincing evidence of a robust zinc transport activity associated with plasma membrane vesicles isolated from rat brain. The results point to a reversible transport of zinc which is highly influenced by pH. These results have led to the following working hypothesis, which forms the conceptual framework for the proposed research. A zinc ion transporter exists in the plasma membrane that mediates both influx and efflux pathways for zinc (i.e., the transporter is freely reversible). The transport mechanism may involve antiport of protons. This zinc ion transporter is present in human brain and its activity may be altered in neurodegenerative disorders such as Alzheimer's Disease. By performing a thorough kinetic analysis of zinc fluxes in human brain plasma membrane vesicles we will find the answers to the following questions, which test the validity of the above hypothesis. 1. Is the zinc transporter present in human brain? 2. What is the mechanism of zinc transport? 3. Do high affinity and low affinity zinc transporters exist? 4. Do major areas of human brain which contain high levels of zinc (e.g., hippocampus), have higher levels of zinc transport activity? 5. Is zinc transporter activity in human brain altered in Alzheimer's Disease?